Neurodegenerative diseases represent an ever-increasing societal and economic burden with WHO estimates indicating that they will replace cancer as the 2nd leading cause of death by 2040. In neurodegenerative disease research, a wealth of pathways has been uncovered, but their direct and primary relevance to the respective human disease has been difficult to prove and targeting of pathways has remained difficult. The proposed work will identify a treatment for spinocerebellar ataxia type 2 (SCA2), a hereditary neurodegenerative disease affecting cerebellar Purkinje cells (PCs) and other neurons in the cerebellum, the subcortical grey matter and spinal cord. The cause of SCA2 is a gain-of-function CAG expansion in the ATXN2 gene resulting in an expanded polyglutamine (polyQ) domain in ataxin-2. Our objective is identification of highly-potent antisense oligonucleotides (ASOs) that lower ATXN2 expression. Our rationale is based on observations in model organisms and humans indicating that higher dosages of the mutant allele/protein worsen disease severity and that down-regulation of mutant polyQ protein expression in rodents reverses clinical manifestations even after mice have become symptomatic. Additionally, complete knock-out of ATXN2 in mice does not cause neurodegeneration or premature death. Merit for this study is supported by positive results in ongoing clinical trials to test ASOs for treating amyotrophic lateral sclerosis (ALS) and myotonic dystrophy type 1 (DM1), as well as the success of SPINRAZA? (Nusinersen) for spinal muscular atrophy (SMA), the first ever FDA approved ASO drug for a neurodegenerative disorder. The feasibility of this study is based on our positive proof-of-concept data demonstrating that our lead ATXN2 ASO delays progressive rodent SCA2 motor, molecular, and neurophysiological phenotypes after symptom onset. Five specific aims are proposed: 1) an intensive in vitro screen of ASOs targeting throughout the ATXN2 pre-mRNA including cultured SCA2 patient cells, 2) in vivo screens to identify leads lowering cerebellar ATXN2 in mice, 3) safety toxicity testing in rodents and other species, 4) testing the ASO leads for delaying established SCA2 mouse motor, molecular, and neurophysiological phenotypes, and 5) GMP manufacturing of the single most potent ASO candidate and pre-investigative new drug (IND) meetings with members of the FDA. The proposed work will break new ground for treatment of neurodegenerative diseases by demonstrating feasibility of targeting dominant-acting mutated polyQ genes with antisense oligonucleotides.